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Probing Origin of Binding Difference of inhibitors to MDM2 and MDMX by Polarizable Molecular Dynamics Simulation and QM/MM-GBSA Calculation.

Chen J, Wang J, Zhang Q, Chen K, Zhu W - Sci Rep (2015)

Bottom Line: Binding abilities of current inhibitors to MDMX are weaker than to MDM2.The predicted binding free energies not only agree well with the experimental results, but also show that the decrease in van der Walls interactions of inhibitors with MDMX relative to MDM2 is a main factor of weaker bindings of inhibitors to MDMX.The analyses of dihedral angles based on MD trajectories suggest that the closed conformation formed by the residues M53 and Y99 in MDMX leads to a potential steric clash with inhibitors and prevents inhibitors from arriving in the deep of MDMX binding cleft, which reduces the van der Waals contacts of inhibitors with M53, V92, P95 and L98.

View Article: PubMed Central - PubMed

Affiliation: School of Science, Shandong Jiaotong University, Jinan, 250014, China.

ABSTRACT
Binding abilities of current inhibitors to MDMX are weaker than to MDM2. Polarizable molecular dynamics simulations (MD) followed by Quantum mechanics/molecular mechanics generalized Born surface area (QM//MM-GBSA) calculations were performed to investigate the binding difference of inhibitors to MDM2 and MDMX. The predicted binding free energies not only agree well with the experimental results, but also show that the decrease in van der Walls interactions of inhibitors with MDMX relative to MDM2 is a main factor of weaker bindings of inhibitors to MDMX. The analyses of dihedral angles based on MD trajectories suggest that the closed conformation formed by the residues M53 and Y99 in MDMX leads to a potential steric clash with inhibitors and prevents inhibitors from arriving in the deep of MDMX binding cleft, which reduces the van der Waals contacts of inhibitors with M53, V92, P95 and L98. The calculated results using the residue-based free energy decomposition method further prove that the interaction strength of inhibitors with M53, V92, P95 and L98 from MDMX are obviously reduced compared to MDM2. We expect that this study can provide significant theoretical guidance for designs of potent dual inhibitors to block the p53-MDM2/MDMX interactions.

No MeSH data available.


Free energy contour map as function of the backbone angle ψ and φ.(A) for Y100 in the pDI6W-MDM2 complex, (B) for Y99 in the pDI6W-MDMX complex. (C) for Y100 in the pDIQ-MDM2 complex and (D) for Y99 in the pDIQ-MDMX complex.
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f7: Free energy contour map as function of the backbone angle ψ and φ.(A) for Y100 in the pDI6W-MDM2 complex, (B) for Y99 in the pDI6W-MDMX complex. (C) for Y100 in the pDIQ-MDM2 complex and (D) for Y99 in the pDIQ-MDMX complex.

Mentions: The free energy landscapes were constructed by using the backbone ψ and φ angle to further probe the conformational change of Y99 (MDMX) relative to Y100 (MDM2), as shown in Fig. 7. The results show that the ψ and φ angle of MDMX generate changes relative to that of Y100. The ψ and φ angle of Y100 in the pDI6W-MDM2 complex are −47° and −58°, which are changed into −32° and −64° in the pDI6W-MDMX complex, respectively. Figure 7C,D suggest that the ψ and φ angle of Y100 correspond to −46° and −58° in the pDIQ-MDM2 complex, while for the pDIQ-MDMX complex, these two angles are transformed into −36° and −63°, respectively. One can note that the alternation of the ψ angle of Y99 in MDMX reaches 10° relative to that of Y100 in MDM2. For the rigid peptide bond, this alternations are great and must produce significant impact on the conformations of the residues nearby.


Probing Origin of Binding Difference of inhibitors to MDM2 and MDMX by Polarizable Molecular Dynamics Simulation and QM/MM-GBSA Calculation.

Chen J, Wang J, Zhang Q, Chen K, Zhu W - Sci Rep (2015)

Free energy contour map as function of the backbone angle ψ and φ.(A) for Y100 in the pDI6W-MDM2 complex, (B) for Y99 in the pDI6W-MDMX complex. (C) for Y100 in the pDIQ-MDM2 complex and (D) for Y99 in the pDIQ-MDMX complex.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663504&req=5

f7: Free energy contour map as function of the backbone angle ψ and φ.(A) for Y100 in the pDI6W-MDM2 complex, (B) for Y99 in the pDI6W-MDMX complex. (C) for Y100 in the pDIQ-MDM2 complex and (D) for Y99 in the pDIQ-MDMX complex.
Mentions: The free energy landscapes were constructed by using the backbone ψ and φ angle to further probe the conformational change of Y99 (MDMX) relative to Y100 (MDM2), as shown in Fig. 7. The results show that the ψ and φ angle of MDMX generate changes relative to that of Y100. The ψ and φ angle of Y100 in the pDI6W-MDM2 complex are −47° and −58°, which are changed into −32° and −64° in the pDI6W-MDMX complex, respectively. Figure 7C,D suggest that the ψ and φ angle of Y100 correspond to −46° and −58° in the pDIQ-MDM2 complex, while for the pDIQ-MDMX complex, these two angles are transformed into −36° and −63°, respectively. One can note that the alternation of the ψ angle of Y99 in MDMX reaches 10° relative to that of Y100 in MDM2. For the rigid peptide bond, this alternations are great and must produce significant impact on the conformations of the residues nearby.

Bottom Line: Binding abilities of current inhibitors to MDMX are weaker than to MDM2.The predicted binding free energies not only agree well with the experimental results, but also show that the decrease in van der Walls interactions of inhibitors with MDMX relative to MDM2 is a main factor of weaker bindings of inhibitors to MDMX.The analyses of dihedral angles based on MD trajectories suggest that the closed conformation formed by the residues M53 and Y99 in MDMX leads to a potential steric clash with inhibitors and prevents inhibitors from arriving in the deep of MDMX binding cleft, which reduces the van der Waals contacts of inhibitors with M53, V92, P95 and L98.

View Article: PubMed Central - PubMed

Affiliation: School of Science, Shandong Jiaotong University, Jinan, 250014, China.

ABSTRACT
Binding abilities of current inhibitors to MDMX are weaker than to MDM2. Polarizable molecular dynamics simulations (MD) followed by Quantum mechanics/molecular mechanics generalized Born surface area (QM//MM-GBSA) calculations were performed to investigate the binding difference of inhibitors to MDM2 and MDMX. The predicted binding free energies not only agree well with the experimental results, but also show that the decrease in van der Walls interactions of inhibitors with MDMX relative to MDM2 is a main factor of weaker bindings of inhibitors to MDMX. The analyses of dihedral angles based on MD trajectories suggest that the closed conformation formed by the residues M53 and Y99 in MDMX leads to a potential steric clash with inhibitors and prevents inhibitors from arriving in the deep of MDMX binding cleft, which reduces the van der Waals contacts of inhibitors with M53, V92, P95 and L98. The calculated results using the residue-based free energy decomposition method further prove that the interaction strength of inhibitors with M53, V92, P95 and L98 from MDMX are obviously reduced compared to MDM2. We expect that this study can provide significant theoretical guidance for designs of potent dual inhibitors to block the p53-MDM2/MDMX interactions.

No MeSH data available.